The Nuffield Department of Medicine is supporting global efforts in tackling nCoV
Introduction – objectives
On 30th January 2020 the World Health Organisation declared the outbreak of novel coronavirus (2019-nCoV) a Public Health Emergency of International Concern.
This international global health emergency requires an immediate and coordinated international response.
The Nuffield Department of Clinical Medicine is supporting global efforts in tackling nCoV. It is prioritising collaborative projects for front line actions. This site’s primary purpose is to provide signposting to projects.
Funding for Oxford’s COVID-19 research requires unprecedented speed, scope and ambition. Please make a gift >>
(i) Professor Peter Horby – clinical characterisation and clinical trials
The UKRI and DHSC funded RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial is led by Peter Horby. Embedded across the NHS, RECOVERY has recruited >10,000 subjects and is now the largest randomised control trial looking at potential treatments for treatment in COVID-19 in hospitalised patients worldwide. RECOVERY provided the first robust evidence that Hydroxychloroquine is not an effective Covid-19 treatment and clear evidence that dexamethasone is effective in reducing mortality by up to 35% in patients on oxygen or ventilated. This is the first treatment shown to reduce mortality in COVI19 disease. The use of dexamethasone, which is cheap, will directly save 10,000’s of lives worldwide. We hope RECOVERY will remain embedded in the NHS as a vehicle for testing new treatments for respiratory infections over coming years.
ISARIC is a world-wide, grass-roots consortium of clinical research networks, working on epidemic infections such as pandemic influenza, Ebola, Lassa fever, and plague. With funding from the Wellcome Trust, the UK Department for International Development, and the Bill & Melinda Gates Foundation, ISARIC has implemented a series of initiatives including collaborative inter-epidemic research studies, pre-positioning of ‘epidemic’ research protocols, responsive research during outbreaks, career development fellowships and training. This initiative was a recognition that research on epidemic infections is difficult: outbreaks are unpredictable in their timing, location and magnitude, they start and finish quickly, they often occur in resource-poor settings, and the outbreak itself disrupts the delivery of healthcare.
ISARIC has played a critical role in the speed of the international scientific response to the COVID-19 pandemic. Its protocols were used in the design and execution of the first clinical trials from Wuhan and it has most recently provided a platform for leading UK responses to COVID-19, including the UKRI and DHSC funded ISARIC-4C (Coronavirus Clinical Characterisation Consortium), the world’s largest prospective observational COVID-19 study. Access to the ISARIC protocols and ethical frameworks in the UK has been a major reason for the rapidity of its response and ability to prosecute the pre-clinical development of vaccines and other therapies.
(ii) Professor Sarah Gilbert – Vaccine Development
Professor Gilbert and Professor Teresa Lambe have generated a new adenoviral vectored vaccine using the same technology as the MERS vaccine, which has completed a phase I clinical trial in the UK (NCT03399578), is currently undergoing phase I trials in Saudi Arabia and recently showed good single dose efficacy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643297/). It was unanimously agreed that a vaccine is likely to be our best chance at a new prophylactic approach. Other variant vaccines – RNA/DNA and protein are being sponsored by CEPI.
The team have developed and manufactured the ChAdOx1 nCoV-19 vaccine in our clinical biomanufacturing facility and with the support of an external partner, Advent, have produced enough doses for use in Phase I, II and III clinical trials.
Professor Lambe is leading the biomedical studies and is collaborating with NIH Rocky Mountain Laboratories (RML), Commonwealth Scientific and Industrial Research Organisation (CSIRO), and the Pirbright Institute to complete the animal challenge studies. Following sufficient data from the preclinical studies and previous clinical trials using the ChAdOx1 technology, the newly developed vaccine entered clinical trials in April, in collaboration with Professor Andrew Pollard, Department of Paediatrics. The vaccine has now reached Phase II/III clinical trials and the programme is aiming to recruit 10,000 participants across multiple trial sites in the UK to assess the efficacy of the vaccine.
This work has been generously supported to allow the trial to progress rapidly, and it was decided that the NDM should provide an underwrite of £1m to get the contracts with GMP partners in Italy in place to accelerate the work.
(iii) Professors Dave Stuart and Yvonne Jones – Structure, Drug Screens and Tools
Dave Stuart, Professor of Structural Biology, has been leading the UK’s national synchrotron facility, the Diamond Light Source in pursuit of antibody and small molecule therapeutics directed against the SARS-CoV-2 enzymes and receptors. Our structural biologists have been deploying fragment-based screening at Diamond’s XChem facility and using crowdsourcing a potential COVID-19 treatments.
NDM scientists have been involved in screening the Gates’ ReFRAME library of licensed drugs for effects against the SARS-Cov2 protease and developing neutralising antibodies that bind to the Spike protein to use as potential therapeutics. On the 13th July, a number of media outlets, including BBC News, Sky News and The Independent published a piece outlining how antibodies derived from llamas have been shown to neutralise the SARS-CoV-2 virus in lab tests. This research is the result of a collaboration between scientists from Diamond Light Source, the Rosalind Franklin Institute, Oxford University and Public Health England.
Our objectives are to develop Coronavirus class-specific anti-viral drugs and rapid protocols for developing neutralising antibodies, as part of our plans for future pandemic preparedness. Detailed understanding of viral proteins also provides a platform for vaccine design.
(iv) Professor Alain Townsend - Neutralising Antibodies and Protein Vaccines
Professor Townsend (Radcliffe Department of Medicine) has a collaborator in Thailand who has cloned some plasmablasts for antibody sequencing; he will work with Elma Tchillian (Pirbright) in isolating monoclonal antibodies to the Spike protein; and he will be working with Professor Mark Howarth in the Department of Biochemistry in Oxford to make a protein aggregate vaccine based on the spike protein, but this will take time.
(v) Professor Tao Dong - Protective Immune Response, Broader collaborations and other projects in China
Professor Dong’s group had long term interest in studying the Antigen specific T cells in acute and chronic virus infection, in particular their roles in protection or disease pathogenesis. She has established collaborative networks in China especially with the two largest infectious disease hospitals in Beijing. Since the start of the pandemic, the group has been working with colleagues in oxford and in China, testing samples taken from COVID-19 positive patients, taken at different time points in their illness and trying to understand why some people with a COVID-19 infection are able to fight it off successfully, while others get really ill. The team believes understanding the immune response to COVID-19 is going to be key to defeating it. They recently found broad and strong SARS-Cov-2 specific immune responses in the patients recovered from COVID-19, and identified clusters of target antigens in the virus can be seen by the T cells (doi: https://doi.org/10.1101/2020.06.05.134551). As result of this work Professor Dong’s group, with other immunologists, are developing a diagnostic cocktail consisting the T cell antigen peptides identified, which they think will complimentary to the antibody test at early stage of infection. Other findings from her group including: Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease which was published in JCI Insight early this month (10.1172/jci.insight.139834); Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with disease severity in COVID-19 published in Journal of Infectious Disease (10.1093/infdis/jiaa224) and Clinical and epidemiological features of COVID-19 family clusters in Beijing, China. published in Journal of infection (10.1016/j.jinf.2020.04.018).
In addition, Professor Dong has agreed with Professor Cao Xuetao, as Directors of the CAMS Oxford Instituteand chief scientist for the COI core support funded by CAMS Innovation fund, priories 7 COVID-19 research projects early this year. (https://www.camsoxford.ox.ac.uk/news/coi-prioritising-funding-support-to-the-current-crisis-caused-by-ncov-2019).
Professor Dong has also coordinated a large donation of PPE to Oxford university and hospitals by one our partner University in China Nankai university, including 150,000 N95 and surgical masks and 20,000 nasal swab kits in early April.
Professor Dong also served as panel member for UKRI/NIHR COVID-19 Rapid-Response Initiative and UKRI/NIHR Rolling call Highlight Notice for Covid-19 virus (SARS-CoV-2) research.
(vi) Professors Gavin Screaton and Guy Thwaites – Samples, Data and Neutralising Antibodies
Professor Screaton is experienced in looking at the neutralising antibody responses to Dengue and Zika and well placed to take similar studies for nCoV forward. It is inevitable that the Oxford Clinical Research Unit in Vietnam, OUCRU, will have access to samples and data. Accessing that will have to be managed but is within the capability of the Unit. NDM will support equipping OUCRU for cell sorting if required.
(vii) Professors Derrick Crook & Tim Peto – UK Hospital Setting; Sample Access, BioAid
Professor Crook is assessing the testing landscape at it emerges in the UK. Any potential cases are tested by PHE hand-in-hand with the local NHS service. PHE during this early phase are understandably reluctant to support independent testing of samples. This will change soon once national protocols become well embedded. Locally, we have ethics approval for testing surplus sample and will transparently undertake testing if cases arise in Oxford.
(VIII) PROFESSOR SARAH WALKER – NATIONAL COVID-19 INFECTION SURVEY AND SEROLOGY TESTING
NDM has provided standardised testing for commercial COVID19 antibody kits in work and has developed a high throughput robotic serology testing platform providing data for the Office of National Statistics COVID-19 Infection Survey. The project led by Dave Stuart and Derrick Crook has brought together a wide range of clinical and non-clinical staff, with input from the NHS, the Diamond Light Source and National Synchrotron at Harwell and Rosalind Franklin Institute at Harwell. The same platform has been used to survey UK Biobank and 10,000 NHS staff in Oxford.
The COVID-19 Infection Survey has been jointly designed and managed by ONS and Professor Sarah Walker, who is the Chief Investigator. The survey has already demonstrated declining prevalence of COVID-19 infection in the general population in England from 26 April to date and overall seroprevalence levels of 5-10%. It is currently being extended to cover other devolved administrations and will continue to assess infection and immunity in the general population over the coming months.
(IX) Professors Christophe Fraser, John Todd, Miles Carroll – Pathogen Evolution and Sequencing.
The Wellcome Centre for Human Genetics (WHG) with Christophe Fraser’s group in the Big Data Institute, have designed and tested high-throughput sequencing tool for 2019-nCoV, based on their SARS experience. The WHG has recently established a major collaboration with the Chinese sequencing company, BGI, which has just announced urgent release of its latest ultra-high-throughput sequencer and a 2019-nCoV RT PCR kit. Miles Carroll who recently joined NDM on partial secondment from Public Health England will assist in getting samples. Establishing safe local protocols is going to be a priority. A number of groups in Oxford are contributing to the disease modelling, development of anti-viral agents, structural determination of key nCoV proteins, vaccine development and identification of therapeutic monoclonal antibodies against the virus.
(X) PROFESSOR CHRISTOPHE FRASER – NHS TRACING APP
It's critical to stay on top of Covid-19 transmission with effective testing and tracing. The NHS Tracing App and its variants created by Apple and Google are being introduced in multiple countries thanks to the vision and creativity of Christophe Fraser, Professor of Pathogen Dynamics, and Dr David Bonsall, clinician and researcher, at Oxford's Big Data Institute. Analysis of test and trace on the Isle of Wight suggests the combination of widespread testing and tracing (human and app-based) has worked very well to bring the epidemic under control. The next step is to have more detailed results on the individual interventions to understand how the lessons can be applied to other regions with the prospect of more localised outbreaks. In addition, they need to understand the potential to adapt COVID-19 digital approaches for low income settings, and other communicable diseases at a high risk of onward transmission In principle, the same mobile approach with track and trace could be deployed to address any communicable disease at a high risk of transmission.
(XI) PROFESSOR PAUL KLENERMAN – COVID-19 Pathology programme
A programme led and co-ordinated by Paul Klenerman and involving over 60 groups across MSD aims to provide one of the most comprehensive studies of COVID-19 Disease at a cellular and protein level.
(xII) Professor Emily Chan – Oxford Visiting Professor
Serving as a global and regional platform for research, education, and community knowledge transfer in the areas of disaster and humanitarian medicine, CCOUC has been responding to COVID-19 outbreak by engaging in various research, education, and community knowledge transfer initiatives with local and international academic partners since early February 2020. Relevant resources, tools, projects, and information can be found in this site